This application is in response to the RFA "Development of Biomarkers of Aging", and will rely on the collaborative efforts of 3 independent laboratories to assess the sensitivity and temporal patterns of a multidisciplinary set of biomarkers-of aging in brain or brain-derived structures. At 5 age points in 3 rat strains we will measure neuronal density in the hippocampus (CA1) and dentate gyrus, and in the central and peripheral retina with light microscopy. We will also measure glial cell density and reactivity. In addition, using quantitative electron microscopy we will measure lipofuscin accumulation in neurons and inclusion body accumulation in astrocytes. Using chronic microelectrode recordings from the dentate gyrus of freely-moving animals, we will analyze evoked potential correlates of a conditioning task, at most of the same are points. Similar approaches will subsequently be extended to examine brain aging in mice. This panel of markers will enable us to study: a) the temporal patterns of development of these aging changes; b) the correlations, or lack thereof, among several measures of brain aging during aging; c) the cross-strain and cross-species generality of these variables; d) the patterns of age changes in a simple cortical structure that is apparently important for memory (the hippocampus) in comparison to age changes in a sensory structure (retina) that is embryologically derived from brain tissue, in which aging-dependent changes appear to interact with environmental factors (light); and e) whether non-lethal, functional (physiological/behavioral) measures correlate with neuroanatomical changes, with the goal of developing future non- invasive indices. In addition, this panel of markers will be used to determined whether chronic dietary restriction, which is one of the only treatments known to lifespan in mammals, also retards the rate of brain aging. Defining the effects on rodent brain aging of experimental interventions that alter longevity seems critical for assessing the possible consequences of similar treatments on the quality of life in humans.